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Activation and Inactivation of G Proteins01:22

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Heterotrimeric G proteins are guanine nucleotide-binding proteins. As the name suggests, heterotrimeric G proteins are composed of three subunits: alpha, beta, and gamma. They remain GDP-bound or GTP-bound inside the cells and switch between inactive/active states. The Gα subunit possesses the nucleotide-binding pocket that binds guanine nucleotides and switches between GDP or GTP-bound states. In contrast, the Gꞵ and Gγ subunits are always bound together with high...
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G Protein-Coupled Receptors or GPCRs are membrane-bound receptors that transiently associate with heterotrimeric G proteins and induce an appropriate response to sensory stimuli such as light, odors, hormones, cytokines, or neurotransmitters.
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G-protein coupled receptors are ligand binding receptors that indirectly affect changes in the cell. The actual receptor is a single polypeptide that transverses the cell membrane seven times creating intracellular and extracellular loops. The extracellular loops create a ligand specific pocket which binds to neurotransmitters or hormones. The intracellular loops holds onto the G-protein.
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Different fluorescence-based techniques are used to study the protein dynamics in living cells. These techniques include FRAP, FRET, and PET.
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Updated: May 13, 2025

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Unveiling G-Protein-Coupled Receptor Conformational Dynamics via Metadynamics Simulations and Markov State Models.

Rita A Roessner1, Nicolas Floquet1, Maxime Louet1

  • 1Institut des Biomolécules Max Mousseron (IBMM), UMR5247, CNRS, Université de Montpellier, ENSCM, Pôle chimie Balard, 1919 route de Mende, Montpellier 34095, France.

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|April 24, 2025
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This study reveals how ligands alter the conformational states of G-protein-coupled receptors (GPCRs), like the growth hormone secretagogue receptor (GHSR-1a). The findings provide molecular insights into GPCR activation and drug development for this receptor family.

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Area of Science:

  • Biochemistry
  • Molecular Biology
  • Computational Biology

Background:

  • G-protein-coupled receptors (GPCRs) are crucial signal transducers whose dynamic nature is key to function.
  • Understanding how ligands modulate GPCR conformational changes to direct signaling is a significant challenge.

Purpose of the Study:

  • To develop a generalizable computational protocol for analyzing GPCR conformational landscapes.
  • To investigate the free energy landscape of the growth hormone secretagogue receptor (GHSR-1a) in apo and ligand-bound states.

Main Methods:

  • Utilized metadynamics simulations and Markov state modeling.
  • Computed the free energy landscape of GHSR-1a.
  • Analyzed apo and ligand-bound states with pharmacologically distinct ligands.

Main Results:

  • GHSR-1a populates multiple metastable states, consistent with the multistate GPCR model.
  • Ligand binding alters the energy and transition probabilities of these states.
  • Identified novel intermediate states and elucidated molecular differences between basal and agonist-induced activation.

Conclusions:

  • The developed protocol accurately captures GPCR activation equilibria in unprecedented detail.
  • The findings offer molecular insights into ligand-driven GPCR signaling.
  • The protocol is applicable to all class A GPCRs, aiding pharmaceutical development.